To our knowledge, this is the first RCT performed to assess the effects of co-administration of vitamin E with atorvastatin on insulin sensitivity, blood glucose and lipids in the T2DM patients with hyperlipidemia. PPAR-γ mRNA expression was assessed as the involved pathway in this effect. Our results suggest that atorvastatin along with vitamin E supplementation compared with atorvastatin alone may have beneficial effect on insulin sensitivity by regulation of serum insulin and HOMA-IR through PPAR-γ mRNA up-regulation. Serum HbA1c, 2hPG, TG, and TC more decreased in the A + E than A + P group, but these changes were not statistically significant. We think this may have been due to not enough sample size which make the present study as a pilot one and a larger sample is needed in the future studies.
PPARs belong to the superfamily of nuclear receptors (NRs), which bind to the ligand and then heterodimerize with a retinoid-X-receptor, finally bind to peroxisome proliferative-response element (PPRE) to initiate signaling pathways (9, 21). PPARs have three isotypes including γ, α and β/δ which have tissue-specific distribution with different biological activity (22). PPAR-γ is an isotype which highly expresses at the adipose tissue and regulates gene expression of lipoprotein lipase, glucose transporters such as GLUT4 and adiponectin (23). At the present study, we showed that vitamin E supplementation along with atorvastatin increases PPAR-γ gene expression which is associated with lower insulin resistance. Our result is in agreement with the previous animal study which vitamin E supplementation (50 mg/kg) increased PPAR-γ level in aortae of rabbits fed a cholesterol-rich diet (24). They concluded that the protection effect of vitamin E against atherosclerosis is related to the increase in ATP-binding cassette transporter A1 (ABCA1) gene expression which is a target gene for PPAR-γ.
The effect of 10 mg/kg d oral atorvastatin was compared with the 10 mg/kg d pioglitazone on PPAR-γ gene expression in the heart of rats after a 3-day pretreatment (25). Results showed that both of them up-regulated PPAR-γ gene expression via increase in myocardial 15-deoxy- prostaglandin J2 (15DPGJ2) levels in the rat myocardium. Tocotrienols enhanced the ligand-binding domains of PPARα with the receptor‐interacting motif of PPAR-γ coactivator‐1α (PGC-1α) interaction. Also, they improved whole body glucose usage and insulin sensitivity by up-regulation of PPAR-γ target genes (14). One cell culture study showed that vitamin E, both α and γ-tocopherol, up-regulates adiponectin expression at mRNA and protein level via a mechanism that increases PPAR-γ mRNA through increase in 15DPGJ, as an endogenous ligand (26).
The combination effect of atorvastatin plus vitamin E was studied in dialysis patients (27). Results showed that atorvastatin is effective in the plasma TC, TG, LDL, apo-lipoprotein B and oxidized LDL reduction in these patients. Adding the alpha-tocopherol to atorvastatin had additional value on in vitro LDL oxidization. Our results are in contrast with this study. At our study, mean changes of TG and TC were higher in the atorvastatin plus vitamin E group than atorvastatin alone, but these changes were not significant. This inconclusive result may be due to various diseases. In one study, the effects of pitavastatin and atorvastatin compared on glycemic control and insulin sensitivity in type 2 diabetic patients with hypercholesterolemia (28). Results showed that with the similar effects on lipid profile, mean changes in HbA1c was significantly higher in the pitavastatin than atorvastatin-treated group. Also, pitavastatin lowered the glycoalbumin, FBS and HOMA-IR, significantly. The present study had the same results. Atorvastatin plus vitamin E had more effect in serum insulin and HOMA-IR than atorvastatin treatment, alone.
Another human study assessed the effect of daily supplementation of 800 IU vitamin E in type 2 diabetic patients for 12 week (29). They concluded that vitamin E supplementation can’t improve FBG, lipid profile, HbA1c, serum insulin, and blood pressure in these patients. Patients didn’t receive any drug for lipid control. Vitamin E effect on blood glucose control is controversial. One study showed that consumption of 1600 IU/day α-tochopherol reduced HbA1c levels, significantly (30). Another study on type 1 diabetic patients has shown this reduction by 100 IU vitamin E supplements (31). Other studies with 600 and 900 IU/day vitamin E decreased oxidative stress, HbA1c, serum insulin and HOMA-IR (32, 33).